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How the Body Fires Up a Joint

Mast cells may not be a household word, but their effects are common and despised. These immune cells unleash histamine, an allergy-provoking compound that causes sniffles and swollen eyes. Now a study of mice finds the troublemaker cells embroiled in another miserable malfunction of the immune system: inflammatory arthritis.

In rheumatoid arthritis, a type of inflammatory arthritis, the two prongs of the immune system conspire. One, known as innate immunity, immediately pounces on pathogens with cells that devour germs and inflame tissues. The other, called adaptive immunity, forges antibodies to fight invaders it has encountered. When antibodies go astray, they sometimes destroy the synovium, a cushion wedged between bones in joints. Researchers think this begins when antibodies are somehow generated against a protein in the synovium. These so-called autoantibodies start up inflammatory immune processes. The inflamed cushion swells and eventually hardens to gnarl the joints. Until now, no one knew how the autoantibodies muster inflammation.

David Lee of Harvard Medical School in Boston and colleagues suspected mast cells. The cells have receptors for both autoantibodies and inflammation-inducing proteins known as complement. What's more, mast cells can release inflammatory molecules called cytokines.

To test this idea, the team turned to so-called K/BxN mice, which develop inflammatory arthritis. Serum taken from these animals and injected into mice of almost any other strain will swell their paws. The researchers injected K/BxN serum into mice that lack mast cells as well as littermates with normal immune systems. As expected, the normal mice acquired full-blown arthritis within 10 days. However, mice without mast cells stayed healthy. The team also transplanted mast cells into the mastless mice; if then injected with K/BxN serum, their paws flared with inflammation. Mast cells had spewed their cytokines and other inflammatory chemicals within 2 hours of serum injection, the team reports in the 6 September issue of Science.

The researchers suggest that mast cells residing in synovial tissue are a cellular link between the free-floating autoantibodies and inflammation. Autoantibodies and complement bind to mast cells, the team proposes, which prompts them to dump their cytokines. These and other inflammatory chemicals then summon the inflammation brigade.

The "beautiful study" clearly shows that mast cells are a key link in inflammatory disease, says rheumatologist Cornelia Weyand of the Mayo Clinic in Rochester, Minnesota. However, verifying that the same thing happens in human disease will be extremely difficult, cautions rheumatologist Joseph Craft of Yale University.